In his paper, published in The EMBO Jorunal, Dr Surrallés describes how proteins of the Fanconi/BRCA pathway recognise the presence of genetic mutations in order to repair them. The researchers also found that alteration of this mechanism makes tumour cells much more sensitive to certain drugs. This discovery will make it possible to develop strategies to make tumours more vulnerable to chemotherapy.
One of the main mechanisms responsible for repairing mutations in humans is the cancer-suppressing Fanconi anaemia/BRCA pathway. This mechanism makes it possible for the cells to identify genetic mutations in order to correct them.
If this mechanism does not function correctly, it leads to Fanconi anaemia, a rare genetic disorder characterised by progressive bone-marrow failure, various congenital malformations and a very high risk of cancer.
Furthermore, the proteins of this pathway are largely responsible for the resistance of tumours to many antitumour agents such as cisplatin and other chemotherapeutic agents that kill tumour cells by producing DNA interstrand crosslinks. That is, they identify cellular alterations induced by chemotherapy and correct them, "accidentally" helping the tumour.
Many tumours have molecular anomalies in this pathway. These defects mean the tumours can be treated efficiently using certain antitumour agents. There are at least 13 genes involved in the pathway. Three of these (BRCA2, BRIP1 and PALB2) are responsible for the high proportion of hereditary breast cancers (between 5 and 10% of all breast cancers).
Understanding how this DNA repair pathway works is of great interest to biomedicine, not only for Fanconi anaemia patients, but also for the general cancer population, since it determines the the efficacy of chemotherapy in treating many tumours. However, the involvement of 13 genes in the same pathway makes the study more complexed.
A team of researchers from the UAB's Mutagenesis Group, led by Doctor Jordi Surralés, has identified one of the important unresolved questions regarding this pathway: how the Fanconi anaemia proteins detect the presence of mutations so they can repair them.
The researchers have found that the mutations block the DNA replication process, a process that is necessary, especially in tumour tissues, for the cells to be able to divide and proliferate. By blocking the replication process, the mutations activate a type of enzyme, the ATR kinase, which phosphorylates (introduces phosphate groups into) histone H2AX, a protein present in the chromatin that surrounds the damaged DNA. The phosphorylated histone H2AX indicates the location of the genetic damage to the Fanconi proteins and places them in exactly the right place to repair the DNA.
The researchers have shown that one of the 13 Fanconi proteins, the FANCD2, binds directly to the phosphorylated histone H2AX. The BRCA1 protein also plays a part in this process and, alongside the BRCA2, it is involved in most hereditary breast cancers. So these proteins cooperate in repairing the genetic damage, preserving the stability of the chromosomes and preventing the onset of tumours.
This research will have many implications on biomedicine. The increase in knowledge on this pathway will make it possible to design strategies for the chemosensitisation of tumour cells. Dr Jordi Surallés's team has also observed that many breast cancer cell lines are between two to three times more sensitive to chemotherapy if they have partially inhibited the Fanconi FANCD2 gene expression.
The results of this study, carried out entirely within the UAB Department Of Genetics and Microbiology, will be published in The EMBO Journal. Most of the work was carried out by the post-doctoral researchers Massimo Bogliolo and Alex Lyakhovich. The group directed by Dr Jordi Surallés is funded by the EU commission, the FEDER fund, the Spanish Ministry of Education and Science, the Spanish Ministry of Health and Consumption, Fundación La Caixa, Genoma España and the Centro de Investigación Biomédica en Red en Enfermedades Raras.
Octavi López Coronado | alfa
Immune Defense Without Collateral Damage
23.01.2017 | Universität Basel
The interactome of infected neural cells reveals new therapeutic targets for Zika
23.01.2017 | D'Or Institute for Research and Education
For the first time ever, a cloud of ultra-cold atoms has been successfully created in space on board of a sounding rocket. The MAIUS mission demonstrates that quantum optical sensors can be operated even in harsh environments like space – a prerequi-site for finding answers to the most challenging questions of fundamental physics and an important innovation driver for everyday applications.
According to Albert Einstein's Equivalence Principle, all bodies are accelerated at the same rate by the Earth's gravity, regardless of their properties. This...
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
23.01.2017 | Health and Medicine
23.01.2017 | Physics and Astronomy
23.01.2017 | Process Engineering